title: Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy.
abstract: Distal hereditary motor neuropathies (dHMNs) are a heterogenous group of genetic disorders with length-dependent degeneration of motor axons. Obtaining a genetic diagnosis in patients with dHMN remains challenging. We performed exome sequencing in a diagnostic setting in 12 patients with a clinical diagnosis of dHMN. Potential disease-causing variants in genes associated with dHMN and other forms of inherited neuropathies/motor neuron diseases were validated using Sequenom. The coverage in the genes studied was >95% with an average coverage of >50 times. In none of the patients a mutations was found in genes previously reported to be associated with dHMN. However, in 2/12 patients a recessive mutation in histidine triad nucleotide binding protein 1 (HINT1, recently discovered as a cause of axonal neuropathy with neuromyotonia) was identified. Our results demonstrate the diagnostic value of exome sequencing for patients with inherited neuropathies. The phenotypic spectrum of recessive mutations in HINT1 includes dHMN. HINT1 should be added to the list of genes to check for in dHMN.
authors.affiliation: 1] Vesalius Research Center, VIB, Leuven, Belgium [2] Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Laboratory for Molecular Diagnostics, Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Race
authors.affiliation: Laboratory for Molecular Diagnostics, Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.affiliation: 1] Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium [2] Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium [3] Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: 1] Vesalius Research Center, VIB, Leuven, Belgium [2] Department of Experimental Neurology, Leuven Research Institute for Neurodegenerative Diseases (LIND), KU Leuven, Leuven, Belgium [3] Department of Neurology, University Hospital Leuven, Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.affiliation: 1] Vesalius Research Center, VIB, Leuven, Belgium [2] Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: 1] Vesalius Research Center, VIB, Leuven, Belgium [2] Department of Experimental Neurology, Leuven Research Institute for Neurodegenerative Diseases (LIND), KU Leuven, Leuven, Belgium [3] Department of Neurology, University Hospital Leuven, Leuven, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
mesh_terms: D000595:Amino Acid Sequence; D004252:DNA Mutational Analysis / Q000379:methods*; D059472:Exome / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D017386:Sequence Homology, Amino Acid
chemical_list: C063306:HINT1 protein, human; D009419:Nerve Tissue Proteins